Aug., 1949
REACTION OF ACETYLGLYCINE WITH ETHYLORTHOFORMATE
the combining region of the antibody a positive charge, or two positive charges, close t o the negative charges of the two carboxylate ions of the hapten. The calculated distance between the negative charge of the carboxylate ion and the positive charge (assumed to be a single charge) which is 2.6 8. greater in the antibody is 5.6 8., than the minimum possible distance of approach of complementary charges in the two molecules. A large decrease in combining power with the antibody is observed in the sequence phthalate ion, pyridine-2,3-dicarboxylateion, .pyrazine-2,3dicarboxylate ion. This decrease is interpreted as resulting from hydration of the heterocyclic ions in solution. The energy required to break the hydrogen bonds between a heterocyclic nitrogen atom [CONTRIBUTION FROM
THE VENABLE
2899
and an attached water molecule is calciilated from the hapten-inhibition data to lie between 700 and 850 cal. mole-'. Unusually small steric effects of groups substituted in the phthalate ion have been observed. These observations are interpreted as showing that the antibodies fit only rather loosely about the haptenic group, the diametral dilatation being about 2 A. in the region near the carboxyl ion groups and somewhat larger on the opposite side of the benzene ring. An explanation of the greater looseness of fit of these antibodies than of those in the systems previously studied is presented. PASADENA, CALIFORNIA
CHEMICAL LABORATORY OF
THE
RECEIVED MARCH29, 1949
UNIVERSITY OF NORTHCAROLINA]
Reaction of Acetylglycine with Ethyl Orthoformate in Acetic Anhydride BY RICHARD H. WILEY,OLINH. BORUMAND LEONARD L. BENNETT,J R . ~ Hydrolysis of the imido ester t o acetylglycine rather than glycine is possible by a reaction similar to the Schotten-Baumann reaction in which the mixed anhydride acetylates the amino group more rapidly than i t is hydrolyzed by water. Infrared absorption spectra3show an absorption band a t 5.6 microns characteristic of the anhydride carbonyl ; absence of the characteristic ester carbonyl absorption band a t 5.8 microns and the presence of absorption bands a t 6.0, 8.0, and 8.4 microns attributable to C=N, and C-0 (C unsaturated) linkages by comparison with N-(ethoxyethylidene) -glycine ester. The absorption band a t 5.6 microns, the only band the solid has in common with acetic anhydride, is also observed with phthalimide. This suggests a diacylamino structure for the solid which, how( C H ~ C O ) ~ K C H ~ C O Z+ C Z H (CZHK)~NHCHZCH~OH ~ ever, is not consistent with other data. The The solid, m. p. 103-104°, obtained in the ethyl spectra are given in Figs. 1and 2. orthoformate reaction reacts readily with water to form acetylglycine quantitatively along with Experimental identifiable amounts of ethyl acetate; reacts Reaction of Acetylglycine with Ethyl Orthoformate and with butylamine to form N-butylamides of acetyl- Acetic Anhydride.-Acetylglycine, 50 g., and 260 g. of glycine and acetic acid; and is readily oxidized acetic anhydride were heated together with stirring for min. a t 90" to dissolve whereupon 63 g. of ethyl orthoby permanganate. Analytical data show the 20 formate was added. After heating at 90-100" for one hour addition of one acetyl and one ethyl group to and fractionating, 26-34 g. of product b.p. 126-136" a t acetylglycine. Of several possible structures, 4 mm. was collected. A t 120-130°, 42-43 g. of this fracthe ethoxyethylidene anhydride (A) and the N- tion was obtained. On standing 13-20 g. of solid sepaethyl anhydride (B) are considered likely although rated from this liquid. The solid was separated by filtration, and the liquid purified by washing with potassium neither 0- nor N- alkylation of amides by ethyl permanganate. Thus purified the product had b.p. orthoformate has been established. The struc- 112' a t 3.5 mm. and n% 1.4532 and was similar in reture (A) is indicated by the reaction with water. fractive index and analysis t o the diacetylglycine ethyl The reaction of acetylglycine and ethyl orthoformate in acetic anhydride has been reported to be anomalous in that no 4-ethoxymethylene-5oxazolone is obtained.2 We wish to report the isolation of two new compounds from this reaction. One is diacetylglycine ethyl ester; the other a solid for which the formula CH&(OCzH6)= NCHXO-0-COCHp is proposed. The same diacetyl ester has also been obtained in up to 88% yield from acetylglycine ethyl ester and acetic anhydride with or without pyridine. This ester reacts slowly with water and with butylamine to give acetylglycine N-n-butylamide, previously undescribed and N-n-butylacetamide. The ester is reduced with lithium aluminum hydride to diethylethanolamine.
CH~C(OCZHK)=NCH~CO--O-COCHII
(4 CH,CON( CzH,)CH2CO*COCH, (B) (1) Taken in part from the Ph.D. thesis of L. L. B . ; address, Birmingham, Alabama. (2) Barber, 61 aI,, British Patent 585,089, January 30, 1947.
ester isolated by fractionation from a refluxed mixture of acetylglycine ethyl ester and acetic anhydride with or without pyridine. Anal. Calcd. for CSH.~O,N: C, 51.33; H, 7.00; N, 7.5; mol. wt., 187. Found: C, 51.27; H, 6.80; N,
(3) T h e authors are indebted to Ralph M. Hill and Miss M. F. Bell, Esso Laboratories, Standard Oil Development Co., for pcnerously providing these data.
RICHARD H. WILEY,OLIN H. BORUMAND LEONARD L. BENNETT,JR.,
2900
2 .,-Infrared
Vol. 71
7 8 9 10 11 12 13 14 15 16 Wave length in microns. spectrum of solid, m. p. 103-104° in carbon bisulfide: absorption a t 4.4-5.0, 6.2-7.2 and 11.2-12.0 microns is that of carbon disulfide. 3
4
5
3
4
5
6
100 80
60 40 20 0 2
7 8 9 10 11 12 Wave length in microns. Fig. 2.-Undiluted ethoxyethylideneglycine ester 6
13
14
15
16
picrate of Carbiode and Carbon sample, 8.0; acetyl, 2.23/mol. wt., 187; ethoxyl, 1.07/mol. wt. m. p. 77-77;5'; m. p . 78-79 ; mixed m. p. 76-78 187. Anal. Calcd. for C l ~ H l ~ O ~ N N,a :16.18. Found: N , Characterization of the Diacetyl Ester.-The diacetyl 16.20. ester reacts with butylamine to give (1) N-butylacetamide, identified by comparison of refractive index, n z 5 ~ Characterization of the Solid.-The soGd was recrystal1.4388, and b.p. with that of a synthetic sample, and (2) lized from nitromethane, m. p. 103-104 . acetylglycine N-n-butylamide, m. p. 133-134 from nitroAnal. Calcd. for C8H130aN: C, 51.33; H, 7.00; K, methane. The latter, previously unreported, was also 7.50; mol. wt., 187. Found: C, 51.82; H, 7.07; N, prepared from acetylglycine ethyl ester, m.p. 134- 7.79; mol. wt., 174 =t3 (ebull. in acetone); 177 8 134.5", no depression of mixed m. p. (ebull. in benzene) ; acetyl, 2.08/mol. wt. 187; ethoxyl Anal. Calcd. for C8H1602N: C, 55.8; H, 9.4; N, 0.93/mol. wt. 187; Zerewitinoff active hydrogen, 0. 16.27. Found: C, 55.83; H , 8.84; N, 16.28. Reaction with water or butylamine gave products listed The diacetyl ester, 9.35 g. (0.05 mole), dissolved in 50 above, identified by combustion or neutral equivalent as ml. of anhydrous ether, was added over four hours to a well as mixed m. p. with synthesized samples. Reaction solution of 5.68 g . (0.15 mole) of lithium aluminum with butanol gave acetylglycine n-butyl ester, previously hydride ( M e F l Hydrides Co.) in 100 mlbof anhydrous unreported, b. p. 139-141 ' (4 mm.). ether a t 2-8 . After two hours a t 2-25 , alcohol and Anal. Calcd. for C8H1603N: N, 8.09. Found: N, then water were added to the mixture. The ether layer 8.10. and ether extracts of the residue were combined, the ether Summary removed, and the residue fractionated to give 2/50 g., 42.8% of diethylethanolamine, b.p. 159-161 , Xz5D Acetylglycine reacts with acetic anhydride and 1.4387-1.4390. The b.p. and n D although in only ethyl orthoformate to give N,N-diacetylglycine fair agreement with values previously reported' agree precisely with values observed on a center cut of refrac- ethyl ester, which is also formed from acetylglytionated diethylethanolamine supplied by Carbide and cine ethyl ester and acetic anhydride, and a solid Carbon Chemicals Corporation.6 m.p. 103-104° for which the formula CH&Anal. Calcd. for C6HljON: N, 11.95. Found: N, (OC2H6)=NCH2COOCOCH3is proposed. 12.18. N,N-Diacetylglycine ethyl ester is reduced by The diethylethanolamine was converted to its picrate, lithium aluminum hydride to diethylethanol-
.
(4) Home and Shriner, THIS JOURNAL, 64, 2928 (1932). (5) The authors appreciate the generous gift of this material.
amine. RECEIVED MARCH3, 1949
